Influenza is foremost amongst infectious diseases that are associated with an increased risk for serious complications and death with aging. While annual vaccination is a mainstay of influenza management, vaccine efficacy is only 40 to 60% effective in the elderly population. The population age 65 and older is steadily increasing worldwide and with increased hospitalization and death rates found in the elderly following influenza infection this trend threatens to overwhelm the health care system;a crisis with the looming threat of pandemic influenza. The need for improved vaccine efficacy in the elderly is clear. In this study, we will examine ways to enhance both humoral and cellular immune responses, since both are important for robust protection from influenza infection. Two specific aims are proposed: 1. Determine which adjuvants can enhance the cognate helper activity of CD4 T cells from aged mice, thus improving Ab production. Using an adoptive transfer model, we will screen adjuvants that enhance the production of inflammatory cytokines, such as TNFoc, IL-1 and IL-6 (T/1/6) following immunization. Our hypothesis is that by enhancing production of these inflammatory cytokines in vivo, we can enhance the cognate helper function of aged CD4 T cells and improve humoral responses. 2. Determine how age-related declines in the cell-mediated immune response to influenza vaccination may be enhanced by adjuvants/virosomes in older adults. We will examine the effects of T/1/6 inflammatory cytokines directly on the function of aged CD4+ and CD8+ T cells in response to adjuvants added to killed virus or virosome vaccines. We will also examine the effects of adjuvants screened in Aim 1 on T cell responses to influenza vaccination, including CTL function. Our hypothesis is that these adjuvants will induce the production of inflammatory cytokines by dendritic cells, thus enhancing the effector functions of T cells from older people. This 5-year proposal will determine how age-related declines in the cell-mediated immune response to influenza vaccination may be enhanced by adjuvants in the elderly with a long-term goal to develop useful immunization strategies aimed at improving vaccine efficacy in the aged. The expected results from these pre-clinical studies is the selection of the most potent virosome and/or other adjuvanted influenza vaccine candidates for clinical trials of interpandemic and pandemic vaccines for older adults.